This invention relates to a new synthetic process for producing macrolide immunosuppressant FK-506 type precursor intermediates.
2. Brief Disclosures in the Art
The novel 23-membered tricyclo-macrolide FK-506 isolated and characterized by Tanaka, Kuroda, and co-workers, see JACS, 109, pp. 5031, 1987, and EPO Publication No. 0,184,162, has been shown to possess exceptional immunosuppressive activity. The potential usefulness of such an agent in bone marrow and organ transplantations coupled with its unique structural features has prompted many in the field to initiate an effort towards the total synthesis of FK-506 (1). ##STR1##
A total synthesis of FK-506 has been achieved by Ichiro Shinkai's Process Chemistry Group at Merck & Co., Inc. by R. Volante, D. Askin, et al. as published in J. Am. Chem. Soc., 1989, Vol. 111, 11, p. 1157. A patent application, U.S. Ser. No. 295,877 filed Jan. 11, 1989, claims this synthesis and is hereby incorporated by reference for this particular purpose.
The total synthesis is an extremely elegant and sophisticated work in the field of macrolide chemistry and requires 54 discrete synthetic steps to FK-506 starting from divinyl carbinol.sup.3 and quinic acid.sup.4. See .sup.3 Askin, D.; Volante, R. P.; Reamer, R. A.; Ryan, K. M.; Shinkai, I., Tetrahedron Lett., 1988, 29, p. 277, and .sup.4 Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I., Tetrahedron Lett., 1988, 28, p. 281.
However, to make other potential immunosuppressant derivatives of FK-506 via this synthetic scheme would be very laborious and particularly those derivatives having a different moiety in the C.sub.1 -N.sub.7 position. It would be desirable to possess a short, convenient process to synthesize FK-506 type macrolides from a readily obtainable intermediate in high yield.
There are no known degradation routes disclosed in the literature from FK-506 to a useful synthetic intermediate. In particular, it is not disclosed how to cleave the C.9, C.10 bond cleanly and in high yield, selectively protect the many alcohol functions and selectively adjust C.10 to the aldehyde oxidation state protected as the labile dimethyl acetal. Furthermore, it is not disclosed as to a method by which the C.26-OH could be deacylated, since all attempts to deacylate C.26-OH with C.22 as the ketone leads to decomposition via a retroaldol fragmentation. See Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto, T.; Hashimoto, M.; Taga, T., J. Am. Chem. Soc., 1987, p. 5031.
What is needed in the art is a convenient, relatively low multistep synthesis of an FK-506 degradation intermediate to synthesize other FK-506 type macrolides having different C.sub.1 -N.sub.7 moieties.